Chapter 14 / Modulation of Synaptic Transmission and Neuronal Excitability: Second Messengers 317
Figure 14–10 G protein βγ-subunits can directly bind and
activate GIRK channels.A high-resolution structure of a GIRK
channel (green) interacting with the G protein β-subunit (Gβ, cyan)
and γ-subunit (Gγ, purple). A geranylgeranyl lipid molecule (gg) is
attached to the C-terminus of Gγ. The structure illustrates that Na
+
ions and the phospholipid PIP
2
also bind to the channel, thereby
enhancing channel opening. The pink spheres inside the channel
represent K
+
ions.(Adapted with permission from Whorton and
MacKinnon 2013. Copyright © 2013 Springer Nature.)
细胞外侧
细胞质侧
K
+
Na
+
gg
Gγ
N-terminus
Gβ
N-terminus
磷脂酰肌醇
-4,5-
二磷酸
of voltage-gated Ca
2+
channels in presynaptic terminals
can suppress the release of neurotransmitter.
Cyclic AMP–Dependent Protein Phosphorylation
Can Close Potassium Channels
In the marine mollusk Aplysia, a group of mechanore-
ceptor sensory neurons initiates defensive withdrawal
reflexes in response to tactile stimuli through fast excit-
atory synapses with motor neurons. Certain interneu-
rons form serotonergic synapses with these sensory
neurons, and the serotonin released by the interneu-
rons sensitizes the withdrawal reflex, enhancing the
animal’s response to a stimulus and thus producing a
simple form of learning (Chapter 53).
The modulatory action of serotonin depends on
its binding to a G protein–coupled receptor that acti-
vates a G
s
protein, which elevates cAMP and thus
activates PKA. This leads to the direct phosphoryla-
tion and subsequent closure of the serotonin-sensitive
(or S-type) K
+
channel that acts as a resting channel
(Figure 14–11). Like the closing of the M-type K
+
channel by ACh, closure of the S-type K
+
channel
decreases K
+
efflux from the cell, thereby depolarizing
the cell and decreasing its resting membrane conduct-
ance. Conversely, the opening of the same S-type K
+
channels can be enhanced by the neuropeptide FMR-
Famide, acting through 12-lipoxygenase metabolites
of arachidonic acid. This enhanced channel opening
leads to a slow hyperpolarizing inhibitory postsynap-
tic potential (IPSP) associated with an increase in rest-
ing membrane conductance.
Thus, a single channel can be regulated by distinct
second-messenger pathways that produce opposite
effects on neuronal excitability. Likewise, a resting
K
+
channel with two pore-forming domains in each
subunit (the TREK-1 channel) in mammalian neurons
is dually regulated by PKA and arachidonic acid in
a manner very similar to the dual regulation of the
S-type channel in Aplysia.
Second Messengers Can Endow Synaptic
Transmission with Long-Lasting Consequences
So far, we have described how synaptic second mes-
sengers alter the biochemistry of neurons for periods
lasting seconds to minutes. Second messengers can
also produce long-term changes lasting days to weeks
as a result of alterations in a cell’s expression of specific
genes (Figure 14–12). Such changes in gene expression
result from the ability of second-messenger cascades to
control the activity of transcription factors, regulatory
proteins that control mRNA synthesis.
Some transcription factors can be directly regu-
lated by phosphorylation. For example, the cAMP
response element-binding protein (CREB) is activated
when phosphorylated by PKA, calcium/calmodulin-
dependent protein kinases, PKC, or MAP kinases. Once
activated, CREB enhances transcription by binding to
specific DNA sequences, the cAMP response elements
or CRE, and recruiting a component of the transcrip-
tion machinery, the CREB-binding protein (CBP). CBP
activates transcription by recruiting RNA polymerase
II and by functioning as a histone acetylase, adding
acetyl groups to certain histone lysine residues. The
acetylation weakens the binding between histones and
DNA, thus opening up the chromatin structure and
enabling specific genes to be transcribed. The changes
in transcription and chromatin structure are important
for regulating neuronal development, as well as for
long-term learning and memory (Chapters 53 and 54).
Modulators Can Influence Circuit Function by
Altering Intrinsic Excitability or Synaptic Strength
Most of this chapter has been devoted to understand-
ing the cellular mechanisms and signal transduc-
tion pathways that allow neuromodulator-activated
Kandel-Ch14_0301-0323.indd 317 10/12/20 11:45 AM